Renal cell carcinoma (RCC) arises in the renal cortex and comprises 80-85% of all kidney cancers. Although it only accounts for about 2% of all cancers, the incidence of kidney malignancies has increased over the past three decades. There will be approximately 54,390 newly diagnosed kidney cancer cases and 13,010 estimated deaths in the United States in 2008.1 RCC is refractory to chemotherapy and radiotherapy. Immnotherapy with IFN or high-dose IL-2 have only a 10-20% response rate and are often accompanied by severe side effects. Until recently, three targeted therapeutics, temsirolimus (TORISEL®), sunitinib (SUTENT®), and sorafenib (NEXAVAR®), which target mammalian target of rapamycin (mTOR), receptor tyrosine kinases (RTKs) and Raf kinases, respectively, have been approved to treat advanced human clear cell RCC (ccRCC).2-6
About a forty percent (40%) response rate was achieved in clinical trials for sunitinib (“SU11248”). SU11248 is an orally-available small molecule inhibitor of several class III and class V split-kinase domain receptor tyrosine kinases (RTKs), including VEGFR, PDGFR, FLT3, c-KIT, and RET. SU11248 was approved to treat advanced human ccRCC in 2006, but the mechanism of action is unknown. Moreover, after about one year of treatment, almost all patients develop resistance to SU11248; and the mechanism of resistance also is unknown.